Topical therapies and combination preparations may have
many advantages over systemically administered
analgesics, including the ability to provide effective
analgesia with reduced systemic drug levels, a factor
particularly beneficial to the elderly. Fewer side
effects coupled with convenient and painless
administration results in improved patient acceptance
and compliance, and ease of use may reduce overall
treatment costs. Because they are applied directly to
the target site, topical administration can provide
therapeutic levels in the tissues under the area of
application, with minimal serum levels. Lower systemic
drug levels potentially lower the risk of organ
toxicity. In addition, first pass hepatic metabolism and
other variables associated with the gastrointestinal
tract are avoided. Topical therapy is a viable solution
which often avoids the need for injections when oral
dosing is not feasible because the patient is nauseated
or unconscious.

Existing
commercially-available treatments may have limited
effectiveness and produce relatively frequent adverse
effects. Patients often convey that different
medications will impart distinct analgesic benefits.
Presence of side effects such as insomnia, depression,
anxiety, and fatigue can diminish the patient's quality
of life, and justify a change to a customized therapy.

There is a growing body
of evidence on the efficacy and safety of topical agents
in a variety of pain disorders, including the most
prevalent neuropathic pain conditions. The molecular
basis for the usage of peripheral analgesics in
neuropathic pain and the available clinical trial
evidence for a wide variety of topical agents are
reviewed in an excellent article by Oscar A. de Leon-Casasola,
MD, Department of Anesthesiology and Critical Care
Medicine, Roswell Park Cancer Institute, School of
Medicine and Biomedical Studies, State University of New
York at Buffalo. Agents “that profoundly reduce
neurotransmitter release from nociceptors generating
ectopic pulses, such as topical local anesthetics and
anticonvulsants, may relieve neuropathic pain. Likewise,
increased peripheral sensitivity mediated through the
release of prostaglandin E2 and substance P at the
peripheral level results in spontaneous discharges that
may be inhibited by topical drugs, such as nonsteroidal
anti-inflammatory drugs (NSAIDs)… Additionally, topical
substance P inhibitors and ketamine can reduce the
effects of substance P, while sympathetic afferent
activation can be modified by the topical administration
of a beta-blocker and clonidine. Topical antihistamine
may decrease the release of histamine and serotonin,
thereby limiting the inflammatory process and hindering
vasodilation. Topical opioids can target the opioid
receptors present on nociceptive fibers and mast cells.
Binding of opioid receptors can inhibit the release of
the calcitonin gene-related peptide (CGRP) and substance
P from nerves, thereby preventing the feed-forward
mechanism of pain that typically results in
sensitization at the site of injury (primary
hyperalgesia).” Pentoxifylline has effectively provided
relief for some neuropathic conditions when applied
topically. “Topical tricyclic antidepressants, such as
doxepin and amitriptyline, have demonstrated efficacy in
a number of neuropathic pain states.”

Neuropathic pain is often resistant to opioids, so other
medication classes - such as tricyclic antidepressants,
anticonvulsants, and local anesthetics - are often used.
Central sensitization, or pain “wind-up”, may perpetuate
chronic neuropathic pain even when ongoing peripheral
sensory input is absent. Wind-up is thought to cause
allodynia, hyperalgesia, and hyperpathia. Receptors such
as NMDA, AMPA, and M-glu have recently been identified
for their role in central sensitization and antagonists
of these receptors have produced pain relief.

The analgesic effect of tricyclic antidepressants is
independent of their antidepressant activity and
generally occurs at low doses with onset of pain relief
in one to two weeks. For example, the analgesic effect
of topically applied doxepin hydrochloride in chronic
human neuropathic pain was described in a randomized,
double-blind, placebo-controlled study of 200 adult
patients. Fewer side effects were reported compared with
oral administration.

Diabetic peripheral
neuropathy (DPN) is a common complication of diabetes.
The most frequent form, estimated to affect 50% of
diabetic patients, is a distal symmetric polyneuropathy.
The associated pain, which affects approximately 25% of
DPN patients, can be severe and disabling.

In a 13-week, phase 3,
randomized double-blind controlled trial, 379 adults
with daily symmetric diabetic peripheral neuropathy
(DPN) leg pain of 3 months duration received placebo,
dextromethorphan/quinidine (DMQ) 45/30 mg, or DMQ 30/30
mg, administered once daily for 7 days and twice daily
thereafter. The results of this study demonstrate that
DMQ was more effective than placebo in the treatment of
DPN pain at both dose levels studied.

Pain Med. 2012
Feb;13(2):243-54.Efficacy and safety of
dextromethorphan/quinidine at two dosage levels for
diabetic neuropathic pain: a double-blind,
placebo-controlled, multicenter study.
Click here to access the abstract of this article.

A patient reported that
lower extremity sweating was a reliable predictor of
soon-to-increase painful “sparking” and burning pain. A
trial of topical 2% glycopyrrolate cream (compounded by
a community pharmacist) was instituted, based on reports
of its use in Frey syndrome. During an episode where
both feet were painful and sweating, 2% glycopyrrolate
was applied to the most painful foot, and capsaicin
0.25% to the other. The patient found that treatment
with 2% glycopyrrolate better alleviated the neuropathic
symptoms compared with capsaicin. This case suggests
that hyperhidrosis may be an index symptom for an
underlying pathobiological driver of neuropathic pain in
patients with painful sweating.

This study evaluated the
effects of a topical gel containing baclofen 10 mg,
amitriptyline HCL 40 mg, and ketamine 20 mg in a
pluronic lecithin organogel (BAK-PLO) on numbness,
tingling, and pain caused by chemotherapy-induced
peripheral neuropathy. The study concluded that BAK-PLO
was well tolerated without evidence of systemic toxicity
and appeared to somewhat improve symptoms of CIPN.

Study subjects with
moderate to severe peripheral neuropathic pain found
that use of topical 2% amitriptyline/1% ketamine cream
was well tolerated and was associated with long-term
reduction in perceived pain.

Combinations of synergistic drugs can be customized for
the patient with chronic pain, and topical or
transdermal formulations offer excellent alternatives,
sometimes with fewer side effects compared to the same
drugs when taken orally. A multicenter, double-blind,
randomized, placebo controlled study was conducted to
evaluate the efficacy and safety of amitriptyline 4%/ketamine
2% [NP-H] and amitriptyline 2%/ketamine 1% [NP-L]
topical creams versus placebo in 251 PHN patients. NP-H
was numerically superior to NP-L cream and placebo, and
appears to be the optimal concentration for PHN
treatment. Less than 5% of subjects who applied NP-H had
detectable serum levels of amitriptyline or ketamine.

This study was presented at the 2007 American Pain
Society Annual Meeting, Poster #787

The following article
discusses the use of
topical ketamine 0.5% (5 mg/ml) gel, applied as a thin
film two to three times daily over the skin where pain
was severe. Topical ketamine reduced pain for
patients with postherpetic neuralgia with no systemic
side effects.

Neurology
2003;60:1391-1392Topical ketamine
treatment of postherpetic neuralgia
No abstract available.
Click here to purchase the full article on line.

The following
randomized, double-blind, placebo-controlled study
assessed the analgesic efficacy of topical
administration of 3.3% doxepin hydrochloride, 0.025%
capsaicin or a combination applied daily for 4 weeks in
200 adult patients with chronic neuropathic pain, and
reported that all three preparations significantly
reduced overall pain.